Smokers with the overlapping COPD phenotypes of airflow obstruction, chronic bronchitis or emphysema carry a significantly higher risk of developing lung cancer, as two recent studies indicated that emphysema detected by CT imaging may be a stronger predictor of lung cancer risk than spirometric airflow obstruction. Lung inflammation and excessive extracellular matrix proteolysis have been implicated as mediators of lung injury by tobacco smoke. Furthermore, tobacco smoke-triggered oxidative stress initiates lung inflammation and progressively disrupts cellular signaling involved in maintenance of lung integrity, eventually leading to organ aging and cell senescence. There are as yet no specific treatments for tobacco smoke-induced lung diseases that target the reversal of lung tissue destruction and promote differentiation for protecting lung tissue. Our goal is to develop novel treatments that target COPD progression and lung cancer simultaneously, based on mechanistic studies of molecular pathways that protect lung tissue from the pathogenesis of both tobacco-smoke induced diseases. Our preclinical studies have documented that prostacyclin supplementation protects against tobacco smoke-induced lung diseases, including COPD and the pre-neoplastic changes observed prior to lung cancer. We hypothesize that activation of the prostacyclin - PPAR3 axis with prostacyclin analogues and PPAR3 agonists has cytoprotective effects in tobacco smoke-induced lung disease, leading to concomitant protection from lung destruction in patients with COPD and development of the transition of epithelial dysplasia to cancer. In specific aim 1, we will determine whether PPAR3 signaling enhancement has a pro-differentiation, chemopreventive effect in individuals at risk for lung cancer and decreases lung inflammation in COPD patients. In specific aim 2, we will pursue inflammation biomarkers that characterize responders versus non-responders to PPAR3 modifying therapies. In specific aim 3, we will demonstrate in murine models that PPAR3 signaling enhancing therapies (iloprost or pioglitazone) can diminish tobacco smoke-induced lung injury;thereby decreasing the occurrence of tobacco smoke-induced lung tumors. Because the drugs being studied are already FDA approved with established safety profiles, our research could yield new treatments relatively soon that target the reversal of lung tissue destruction and promote lung tissue protection for the tobacco smoke-induced lung diseases COPD and lung cancer. PUBLIC HEALTH RELEVANCE: Tobacco smoke causes both lung cancer and chronic obstructive pulmonary disease (COPD). There is recent data showing that patients with severe COPD are at an increased risk of developing lung cancer. Our proposal seeks to show that two FDA approved drugs, iloprost and pioglitazone, can not only protect against the progression of precancerous changes but also protect the patients that have COPD. We rely on already ongoing and funded clinical trials to investigate the beneficial effects of both drugs. Our experiments target the identification of biomarkers that can be used to identify those individuals who respond to both drugs. Our experiments also involve state of the art investigations in animal models to clarify how these drugs act to protect the lung.